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Novel insights into lineage specification in the brain

Boyan Bonev and team provide a comprehensive, cell-type specific assessment of the multimodal regulatory landscape of the developing mouse cortex.

The context and problem. The development of the evolutionary youngest structure of the mammalian brain, the cortex, is precisely regulated during embryogenesis in order to faithfully generate highly specialized neurons from progenitor cells. Mis-regulation of this process can have dramatic consequences ranging from embryonic death to severe mental disabilities. Despite its fundamental importance, the exact multi-layered molecular mechanisms leading to acquisition of neural identity, lineage specification and developmental plasticity in the cerebral cortex have remained elusive.

In the cell, a complex interplay between transcriptional factors and the chromatin landscape takes place within the physical 3D constraints of the cell nucleus, ensuring the precise temporal and spatial control of gene expression. Regulatory layers often converge on enhancer elements - genomic sequences which positively regulate gene expression, yet their functional contribution to lineage specification in the brain remains unclear. Many enhancers are also frequently associated with neurodevelopmental disorders, but the vast majority have yet to be characterized in vivo due to the immense complexity and heterogeneity of the mammalian cortex.

The solution and results. Combining single-cell transcriptomic and epigenomics, as well as cell-type-specific bulk DNA methylation and 3D genome architecture in vivo, the Bonev group now provides comprehensive and cell-type specific assessment of how coordinated epigenome remodelling governs neuronal differentiation in the developing neocortex.

In a recent study, published in Nature Neuroscience, the team profiled more than 10.000 single cells isolated from murine embryonic brains and not only mapped ~ 16.000 dynamically regulated enhancers, but also associated them to their target genes. Building on this comprehensive dataset of the cortex-specific gene regulatory networks, the authors identified several transcription factors which are associated with widespread rewiring of enhancer activity in different cell lineages.

To directly test if the identified transcription factors are responsible for the dynamic enhancer activity, the group developed a novel cell-type specific massive parallel reporter assay, which allows for simultaneous measurements of thousands of enhancer sequences in vivo. This comprehensive analysis represents the largest effort to date to characterize enhancer activity in vivo and provides an unbiased and entirely new viewpoint of how enhancer activity is regulated during cortical development.

By integrating this data with genome-wide maps of 3D chromatin interactions and DNA methylation in purified cell populations in vivo, the researchers were also able to map enhancers to their target genes based on physical proximity and pinpoint dynamic chromatin looping as an additional novel regulatory mechanism during cell lineage decisions. Finally, they identified and functionally validated in vivo a neuronal transcription factor (Neurogenin 2) as a key epigenetic modulator that coordinates the remodelling of multiple epigenetic layers in order to promote neuronal differentiation.

Importantly, the Bonev team built a cus­tom web­site for interactive visualisation of their results to facilitate exploration of the data even for people without prior computational knowledge.

The future. These findings substantially improve our molecular knowledge of brain development and provide novel insights into how epigenetic regulatory layers can be coordinated to facilitate robust lineage decisions. Contrasting and comparing these results with studies in the human brain and expanding them to study temporal cell fate regulation will advance our understanding of non-coding disease-associated mutations and one day allow us to decipher the complete regulatory logic of brain development. As such, this ground-breaking study provides a much-needed impulse towards novel therapeutic targets for neurodevelopmental diseases and gene therapies in the future.

(Text: Helmholtz Pioneer Campus, HPC)

Publication: Noack et al.: Multimodal profiling of the transcriptional regulatory landscape of the developing mouse cortex identifies Neurog2 as a key epigenome remodeler, Nature Neuroscience 2022